An enantioselective total synthesis of (-)-chlorothricolide (1) has been completed via a route involving the tandem inter- and intramolecular Diels-Alder (IMDA) reaction of hexaenoate 19 and the chiral dienophile (R)-12. This reaction, which establishes seven asymmetric centers in a single operation, is feasible only by virtue of the high diastereofacial and exo selectivity of dienophile 12. The C(9)-trimethylsilyl steric directing group of 19 also plays a key role by controlling the stereochemical course of the IMDA reaction leading to the bottom half octahydronaphthalene unit. Hexaenoate 19 was prepared in 32% overall yield by a 10-step sequence starting from the known acetylenic ketone 33. Key steps include the asymmetric reduction of 33 using Alpine Borane (up to 94% eel, the Suzuki cross coupling of a-iodo vinylsilane 20 with vinylboronic acid 21, and the Homer-type olefination of aldehyde 41 with dienylic phosphonate 22. The key tandem inter-intramolecular Diels-Alder reaction was performed by heating a mixture of 19 and (R)-12 (2 equiv) in toluene at 120 degrees C, which provided the targeted double cycloadduct 44 in 40-45% yield, along with 19% of other cycloadduct isomers and 25-20% of the IMDA adduct 24 with an (E,E,E)-C(16)--C(21) triene. The latter compound was recycled by treatment with additional (R)-12 in trichloroethylene at 125 degrees C. The yield of 44 from hexaenoate 19 was 55-59% after one recycle of (E,E,E)-24. Elaboration of 44 to (-)-chlorothricolide was accomplished by a 9-step sequence in 26% overall yield, key steps of which included the construction of the spirotetronate subunit of 51 via the Dieckmann cyclization of 50, deprotection of the two allyl units with Pd(0) catalysis, and the BOP-Q-mediated macrolactonization of seco acid 52. The vinyl trimethylsilane substituent was removed in the final step of the synthesis by treatment with EtSH and BF3.Et2O. Because an authentic sample of chlorothricolide was not available, synthetic (-)-chlorothricolide was treated with CH2N2 to give 24-O-methyl chlorothricolide methyl ester (59) [[alpha]D-25 -29.3 degrees (c = 0.95, CHCl3), mp 228.5-229 degrees C; lit.(1a) [alpha]D-20 - 30 degrees (c = 1, CHCl3), lit.(1a) mp 230 degrees C)] which proved identical in all respects (except optical rotation and mp) with an authentic sample of racemic 59 provided by Professor Yoshii.